DESCRIPTION (provided by principal investigator): This is a resubmission of grant application 1 R01 NS061836-01, now entitled "Whole Genome Association Study of Migraine in Women," which is a response to program announcement PA-07-305. In this application, we request funding to conduct a genome-wide association study of migraine and migraine traits within a large prospective cohort of more than 27,000 women, of whom more than 5,000 reported migraine. DNA from blood samples of all participants is presently undergoing a whole genome scan using the Illumina platform. In addition, extensive plasma-based phenotyping has been performed. Approximately 20 percent of the population suffers from migraine headaches;however, at any age, women are affected 3 to 4 times more often than men. Migraines account for most pain-related emergency room visits, and may persist as a chronic condition throughout the lifespan. Despite the high prevalence of migraine and a long history of relevant research, many questions remain regarding the pathophysiology and the multitude of endogenous and exogenous factors that influence this complex disorder. Gene mutations for rare forms of migraine have been recently identified. While linkage analyses have identified chromosomal loci in common forms of migraine, the underlying genes are unknown. In addition, candidate gene approaches in common forms of migraine have been disappointing, mainly due to lack of replication and small samples sizes. Thus, the genetic causes for common forms of migraine remain elusive. We propose 1) to identify novel candidate genetic variants/genes of migraine using (i) a conventional genome-wide association approach and (ii) a novel weighted genome-wide association approach that utilizes information from previously proposed chromosomal loci and 2) to explore interactions between identified candidate genetic variants/genes of migraine with biomarkers and environmental factors. We further propose two secondary aims in which we extend the evaluation of our primary aims to migraine traits, in particular migraine aura status. To achieve these aims, we propose to utilize information from the Women's Health Study (WHS), a large, well-characterized cohort of women 45 years of age and older in 1993. DNA has been extracted from collected blood samples from 27,939 women, and a whole genome scan of all available DNA samples is underway and expected to be completed by December 2008. At baseline and during follow-up, over 5,000 women reported migraine. In contrast to other large cohorts of US women, the WHS is an extraordinary resource that not only has extensive data on many traditional epidemiologic exposures, but also detailed information about migraine. Furthermore, plasma-based phenotyping is available on an exceptionally large number of samples. Thus, the WHS is particularly suited to study the genomics of migraine as well as gene-gene, gene-biomarker, and gene-environment interactions in a very cost-effective way. PUBLIC HEALTH RELEVANCE Migraine is a very common headache disorder that particularly affects women. Despite a large body of research, little is know about the pathophysiology and the multitude of endogenous and exogenous factors that influence this complex disorder. Although recently gene mutations for rare forms and candidate genes for more common forms of migraine have been identified, the mode of inheritance has only been established a very rare migraine form. Thus, we request funding to study the genomic of migraine using a whole genome approach and to evaluate gene-environment interactions.